Leptin found to control appetite and limb development in frogs

ANN ARBOR, Mich.---Leptin, the hormone secreted by fat cells that plays an important role in food intake, has been described for the first time in a cold-blooded vertebrate, the South African clawed frog Xenopus.

As it does in humans and other mammals, leptin acts on the frog brain to suppress appetite. But the hormone also seems to play a role in the complex signaling that turns a finned tadpole into a four-legged frog, according to Robert Denver, an associate professor of biology at the University of Michigan.

Denver's team gave frogs a dose of leptin at various stages of development from tadpole to near adult and watched what happened. As in mice, the hormone is apparently a powerful appetite suppressant for these animals, causing them to give up eating even as their bodies waste away.

But the youngest tadpoles showed a different response to the hormone. Rather than going off their feed as the older frogs did, these tadpoles kept right on eating and quickly sprouted limbs.

Denver, who has studied the ability of frogs to speed up their metamorphosis in response to a drying pond, thinks that the tadpoles' feeding mechanism is stuck in the "on" position at the first stages of life, because they need to eat and grow as fast as possible to avoid being prey. For these tadpoles, the leptin signal isn't capable of turning the feeding behavior off, but it does apparently tell their bodies that they've had enough to eat now, and they can begin sprouting limbs.

"Leptin gets a lot of attention for its role in food intake, but it's clear that it does lots of other jobs," he said. The hormone is known to be part of a family of proteins called cytokines that includes pituitary growth hormone, and it has been found to increase cell proliferation in the brains of rats.

Leptin is also found in late-stage fetal humans, mice, and sheep, and appears to be linked to birth weight, but little is known about what role it might be playing overall in fetal growth and development.

Denver's study showed that there are receptors in the tadpole's waiting limbs that crank up cell division when leptin signals are received. "This hormone sets the stage for growth, both signaling to the brain that there are sufficient energy stores and perhaps directly promoting tissue growth and development." The timing of metamorphosis in frogs is central to their survival, Denver said. If tadpoles metamorphose too soon they are at a body size disadvantage with little fat reserves. They pay the cost of immediate survival by being more prone to drying out, to being eaten by predators and reaching sexual maturity at a later age. Denver speculates that leptin is probably important to gauge whether the tadpole has adequate energy reserves---in the form of body fat - to start metamorphosis at an appropriate time.

Finding leptin in the Xenopus genome was no small feat. The sequence for the "obese" gene that makes leptin is quite different between frogs and humans, so Denver's lab had some puzzles to solve to successfully clone the frog gene. But once they solved those issues and put the gene into E. coli bacteria to make quantities of leptin, the frog protein turned out to be functionally very similar to the human version, Denver notes.

"It would appear that leptin and its role as an energy balance indicator has been around a long time," Denver said. "Leptin's other roles in animal development are just beginning to be understood."

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The paper "Leptin (ob gene) of the South African clawed frog Xenopus laevis" appears in the on-line addition of the Proceedings of the National Academy of Sciences the week of June 12. The work was supported by the National Science Foundation.